The overall goal of this project is to engineer novel biodegradable cationic polymers for intracellular delivery of nucleic acid materials to antigen presenting cells (APCs) for cancer immunotherapy applications. Immune cells are conventionally very difficult to transfect, and the most successful platforms to date are viral vectors, which are powerful gene delivery vehicles but have important safety concerns associated with their use in humans. Non-viral vectors are safer and less immunogenic alternatives to viral vectors and have a larger carrying capacity. However, their success in transfecting immune cells has been somewhat limited. The novel system developed in this work will address the challenges associated with intracellular delivery to APCs to achieve targeted and efficient delivery of nucleic acids using safe, biodegradable materials. Biodegradable polymeric nanoparticles will be developed for both DNA (Specific Aim 1) and mRNA (Specific Aim 2) delivery to immune cells, specifically APCs, for two cancer immunotherapy applications. In Specific Aim 1, polymers will be developed for DNA delivery to macrophages in order to develop a macrophage repolarization therapy for breast cancer treatment. Tumor associated macrophages (TAMs) are abundant in many cancers and typically display an M2 phenotype that is immunosuppressive and pro- tumorigenic. However, the phenotype of macrophages is highly plastic and, as such, they can be converted to a more immunostimulatory and anti-tumorigenic M1 phenotype. Breast cancer is the leading cause of new cancer cases and cancer deaths in women, and TAMs have been found to play an important role in the immunosuppressive nature of breast cancer tumor microenvironment and drug resistance. In Specific Aim 2, I will engineer novel polymeric nanoparticles to deliver mRNA to dendritic cells for a genetic vaccine for melanoma. Metastatic melanoma is major health concern with increasing prevalence and a poor five-year survival rate. Genetic cancer vaccines are a promising strategy to treat melanoma, as it is a highly immunogenic cancer, that utilize the body?s own defense mechanisms by causing dendritic cells to endogenously produce tumor-associated antigen and present it to T cells. Genetic vaccines have distinct advantages over conventional vaccines, such as antigen presentation by both MHC I and MHC II, ease and cost of production, safety, and longer-term persistence of the immunogen. However, there is a need for increased potency in order for genetic vaccines to be effective in humans. This research aims to develop novel polymers that address the challenges associated with nucleic acid delivery to dendritic cells to develop an enhanced genetic vaccine for melanoma. Overall, the research proposed here will lead to significant progress in the field of gene delivery by developing modular polymeric nanoparticles that can be used to deliver various types of nucleic acid materials to APCs in vitro and in vivo for cancer immunotherapy applications.